Molecular Complexity-Inspired\nSynthetic Strategies\ntoward the Calyciphylline A‑Type <i>Daphniphyllum</i> Alkaloids Himalensine A and Daphenylline

In this report, we detail two distinct synthetic approaches\nto\ncalyciphylline A-type <i>Daphniphyllum</i> alkaloids himalensine\nA and daphenylline, which are inspired by our analysis of the structural\ncomplexity of these compounds. Using MolComplex, a Python-based web\napplication that we have developed, we quantified the structural complexity\nof all possible precursors resulting from one-bond retrosynthetic\ndisconnections. This led to the identification of transannular bonds\nas especially simplifying to the molecular graph, and, based on this\nanalysis, we pursued a total synthesis of himalensine A from macrocyclic\nintermediates with planned late-stage transannular ring formations.\nDespite initial setbacks in accessing an originally designed macrocycle,\ntargeting a simplified macrocycle ultimately enabled investigation\nof this intermediate’s unique transannular reactivity. Given\nthe lack of success to access himalensine A based solely on molecular\ngraph analysis, we revised our approach to the related alkaloid, daphenylline.\nHerein, we also provide the details of the various synthetic challenges\nthat we encountered and overcame en route to a total synthesis of\ndaphenylline. First, optimization of a Rh-mediated intramolecular\nBuchner/6π-electrocyclic ring-opening sequence enabled construction\nof the pentacyclic core. We then describe various attempts to install\na key quaternary methyl group and, ultimately, our solution to leverage\na [2 + 2] photocycloaddition/bond cleavage sequence to achieve this\nelusive goal. Finally, a late-stage Friedel–Crafts cyclization\nand deoxygenation facilitated the 11-step total synthesis, which was\nmade formally enantioselective by a Rh-mediated dihydropyridone conjugate\narylation. Complexity analysis of the daphenylline synthesis highlights\nhow complexity-building/C–C cleavage combinations can be uniquely\neffective in achieving synthetic outcomes.